PUBLICATION
Live imaging of neutrophil motility in a zebrafish model of WHIM syndrome
- Authors
- Walters, K.B., Green, J.M., Surfus, J.C., Yoo, S.K., and Huttenlocher, A.
- ID
- ZDB-PUB-100702-17
- Date
- 2010
- Source
- Blood 116(15): 2803-2811 (Journal)
- Registered Authors
- Huttenlocher, Anna, Walters, Kevin
- Keywords
- none
- MeSH Terms
-
- Agammaglobulinemia/genetics
- Amino Acid Sequence
- Animals
- Animals, Genetically Modified
- Cell Movement
- Chemokine CXCL12/genetics
- Chemotaxis, Leukocyte
- Disease Models, Animal
- Gene Expression
- Hematopoiesis
- Humans
- Immunologic Deficiency Syndromes/genetics
- Immunologic Deficiency Syndromes/pathology
- Molecular Sequence Data
- Mutation
- Neutropenia/genetics*
- Neutropenia/pathology*
- Neutrophils/pathology
- Neutrophils/physiology*
- Receptors, CXCR4/genetics
- Signal Transduction
- Syndrome
- Zebrafish
- Zebrafish Proteins/genetics
- PubMed
- 20592249 Full text @ Blood
Citation
Walters, K.B., Green, J.M., Surfus, J.C., Yoo, S.K., and Huttenlocher, A. (2010) Live imaging of neutrophil motility in a zebrafish model of WHIM syndrome. Blood. 116(15):2803-2811.
Abstract
CXCR4 is a G-protein coupled chemokine receptor that has been implicated in the pathogenesis of primary immunodeficiency disorders and cancer. Autosomal dominant gain-of-function truncations of CXCR4 are associated with warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome, a primary immunodeficiency disorder characterized by neutropenia and recurrent infections. Recent progress has implicated CXCR4-SDF1 signaling in regulating neutrophil homeostasis but the precise role of CXCR4-SDF1 interactions in regulating neutrophil motility in vivo is not known. Here, we utilize the optical transparency of zebrafish to visualize neutrophil trafficking in vivo in a zebrafish model of WHIM syndrome. We demonstrate that expression of WHIM mutations in zebrafish neutrophils induces neutrophil retention in hematopoietic tissue, impairing neutrophil motility and wound recruitment. The neutrophil retention signal induced by WHIM truncation mutations is SDF1 dependent, since depletion of SDF1 using morpholino oligonucleotides restores neutrophil chemotaxis to wounds. Moreover, localized activation of a genetically encoded, photoactivatable Rac GTPase is sufficient to direct migration of neutrophils that express the WHIM mutation. The findings suggest that this transgenic zebrafish model of WHIM syndrome may provide a valuable tool to screen for agents that modify CXCR4-SDF1 retention signals.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping